The 5-HT7 receptor is one of the more recently discovered receptors for serotonin (5-HT). It is found both in the central nervous system and in peripheral tissues. This receptor has been implicated in many physiological and pathological mechanisms. Examples include regulation of circadian rhythm, learning and memory, temperature homeostasis, sleep regulation, and neuropsychiatric disorders, especially mood disorders. Recent years have shown a steady increase in our knowledge of 5-HT7 receptor function. This has been made possible by the availability of selective antagonists and knockout mice strains. One of these strains was generated by us and its use has led to several important discoveries. We have been able to more clearly map the distribution of 5-HT7 receptors in the brain, describe in detail the role of this receptor in 5-HT-mediated thermoregulation, and discovered a role for the 5-HT7 receptor in learning and memory. Pharmacological and behavioral studies have suggested a role for the 5-HT7 receptor in affective and psychotic diseases. We propose to investigate these hypotheses using animal models that have been shown to have predictive value for assessing the efficacy of drugs in treating depression or schizophrenia. The animal models to be used are the forced swim test and the tail suspension test to evaluate depression. Preliminary data show that mice lacking the 5-HT7 receptor are in a more "anti-depressed" state in these tests. We will also investigate the role of the 5-HT7 receptor in hippocampal neurogenesis, a phenomenon of importance for depression. For schizophrenia the acoustic startle reflex with prepulse inhibition (PPI) will be used. Preliminary data show that 5-HT7 receptor knockout mice are less susceptible to drug-induced disruption of PPI. These studies will provide valuable data for possible improvements of the therapy for disorders that afflicts large groups of the population.